Bottom Line:
The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation.Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects.PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue.

ABSTRACTThe pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases.

fig1: Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.

Mentions:
PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been characterized within the promoter regions of PPAR target genes. The binding occurs in such a way that PPAR is always oriented to the DNA's 5′-end, while RXR is oriented to the 3′-end. In the absence of a ligand, high-affinity complexes are formed between PPAR-RXR heterodimers and nuclear receptor corepressor proteins, which block transcriptional activation by sequestering the heterodimer from the promoter.

fig1: Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.

Mentions:
PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been characterized within the promoter regions of PPAR target genes. The binding occurs in such a way that PPAR is always oriented to the DNA's 5′-end, while RXR is oriented to the 3′-end. In the absence of a ligand, high-affinity complexes are formed between PPAR-RXR heterodimers and nuclear receptor corepressor proteins, which block transcriptional activation by sequestering the heterodimer from the promoter.

Bottom Line:
The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation.Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects.PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue.

ABSTRACTThe pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases.